High MMP-9 activity characterizes pleural tuberculosis correlating with granuloma formation

Tuberculosis (TB) pleural disease is complicated by extensive tissue destruction. Matrix metalloproteinase (MMP)-1 and -9 are implicated in immunopathology of pulmonary and central nervous system TB. There are few data on MMP activity in TB pleurisy. The present study investigated MMP-1, -2 and -9 and their specific inhibitors (tissue inhibitor of metalloproteinase (TIMP)-1 and -2) in tuberculous effusions, and correlated these with clinical and histopathological features. Clinical data, routine blood tests, and pleural fluid/biopsy material were obtained from 89 patients presenting with pleural effusions in a TB-endemic area. MMP-1, -2 and -9 were measured by zymography or western blot, and TIMP-1 and -2 by ELISA. Pleural biopsies were examined microscopically, cultured for acid–alcohol fast bacilli and immunostained for MMP-9. Tuberculous pleural effusions contained the highest concentrations of MMP-9 compared with malignant effusions or heart failure transudates. MMP-9 concentrations were highest in effusions from patients with granulomatous biopsies: median (interquartile range) 108 (61–218) pg·mL-1 versus 43 (12–83) pg·mL-1 in those with nongranulomatous pleural biopsies. MMP-1 and -2 were not upregulated in tuberculous pleural fluid. The ratio of MMP-9:TIMP-1 was significantly higher in TB effusions. Tuberculous pleurisy is characterised by a specific pattern of matrix metalloproteinase-9 upregulation, correlating with the presence of granulomas and suggesting a specific role for matrix metalloproteinase-9 in inflammatory responses in tuberculous pleural disease.

STAT3, p38 MAP Kinase and NF-{kappa}B Drive Unopposed Monocyte-dependent Fibroblast MMP-1 Secretion in Tuberculosis.

Tissue destruction characterizes infection with Mycobacterium tuberculosis (Mtb). Type I collagen provides the lung's tensile strength, is extremely resistant to degradation, but is cleaved by matrix metalloproteinase (MMP)-1. Fibroblasts potentially secrete quantitatively more MMP-1 than other lung cells. We investigated mechanisms regulating Mtb-induced collagenolytic activity in fibroblasts in vitro and in patients. Lung fibroblasts were stimulated with conditioned media from Mtb-infected monocytes (CoMTb). CoMTb induced sustained increased MMP-1 (74 versus 16 ng/ml) and decreased tissue inhibitor of metalloproteinase (TIMP)-1 (8.6 versus 22.3 ng/ml) protein secretion. CoMTb induced a 2.7-fold increase in MMP-1 promoter activation and a 2.5-fold reduction in TIMP-1 promoter activation at 24 hours (P = 0.01). Consistent with this, TIMP-1 did not co-localize with fibroblasts in patient granulomas. MMP-1 up-regulation and TIMP-1 down-regulation were p38 (but not extracellular signal–regulated kinase or c-Jun N-terminal kinase) mitogen-activated protein kinase–dependent. STAT3 phosphorylation was detected in fibroblasts in vitro and in tuberculous granulomas.STAT3 inhibition reduced fibroblast MMP-1 secretion by 60% (P = 0.046). Deletion of the MMP-1 promoter NF-B–binding site abrogated promoter induction in response to CoMTb. TNF-, IL-1ß, or Oncostatin M inhibition in CoMTb decreased MMP-1 secretion by 65, 63, and 25%, respectively. This cytokine cocktail activated the same signaling pathways in fibroblasts and induced MMP-1 secretion similar to that induced by CoMTb. This study demonstrates in a cellular model and in patients with tuberculosis that in addition to p38 and NF-B, STAT3 has a key role in driving fibroblast-dependent unopposed MMP-1 production that may be key in tissue destruction in patients.

A scalable packet sorting circuit for high-speed WFQ packet scheduling

A novel implementation of a tag sorting circuit for a weighted fair queueing (WFQ) enabled Internet Protocol (IP) packet scheduler is presented. The design consists of a search tree, matching circuitry, and a custom memory layout. It is implemented using 130-nm silicon technology and supports quality of service (QoS) on networks at line speeds of 40 Gb/s, enabling next generation IP services to be deployed.

Fully hardware based WFQ architecture for high-speed QoS packet scheduling

A full hardware implementation of a Weighted Fair Queuing (WFQ) packet scheduler is proposed. The circuit architecture presented has been implemented using Altera Stratix II FPGA technology, utilizing RLDII and QDRII memory components. The circuit can provide fine granularity Quality of Service (QoS) support at a line throughput rate of 12.8Gb/s in its current implementation. The authors suggest that, due to the flexible and scalable modular circuit design approach used, the current circuit architecture can be targeted for a full ASIC implementation to deliver 50 Gb/s throughput. The circuit itself comprises three main components; a WFQ algorithm computation circuit, a tag/time-stamp sort and retrieval circuit, and a high throughput shared buffer. The circuit targets the support of emerging wireline and wireless network nodes that focus on Service Level Agreements (SLA's) and Quality of Experience.

Impact of nitrogen seeding on confinement and power load control of a high-triangularity JET ELMy H-mode plasma with a metal wall

This paper reports the impact on confinement and power load of the high-shape 2.5 MA ELMy H-mode scenario at JET of a change from all carbon plasma-facing components to an all metal wall. In preparation to this change, systematic studies of power load reduction and impact on confinement as a result of fuelling in combination with nitrogen seeding were carried out in JET-C and are compared with their counterpart in JET with a metallic wall. An unexpected and significant change is reported on the decrease in the pedestal confinement but is partially recovered with the injection of nitrogen.

ELM-induced transient tungsten melting in the JET divertor

The original goals of the JET ITER-like wall included the study of the impact of an all W divertor on plasma operation (Coenen et al 2013 Nucl. Fusion 53 073043) and fuel retention (Brezinsek et al 2013 Nucl. Fusion 53 083023). ITER has recently decided to install a full-tungsten (W) divertor from the start of operations. One of the key inputs required in support of this decision was the study of the possibility of W melting and melt splashing during transients. Damage of this type can lead to modifications of surface topology which could lead to higher disruption frequency or compromise subsequent plasma operation. Although every effort will be made to avoid leading edges, ITER plasma stored energies are sufficient that transients can drive shallow melting on the top surfaces of components. JET is able to produce ELMs large enough to allow access to transient melting in a regime of relevance to ITER.

Transient W melt experiments were performed in JET using a dedicated divertor module and a sequence of I-P = 3.0 MA/B-T = 2.9 T H-mode pulses with an input power of P-IN = 23 MW, a stored energy of similar to 6 MJ and regular type I ELMs at Delta W-ELM = 0.3 MJ and f(ELM) similar to 30 Hz. By moving the outer strike point onto a dedicated leading edge in the W divertor the base temperature was raised within similar to 1 s to a level allowing transient, ELM-driven melting during the subsequent 0.5 s. Such ELMs (delta W similar to 300 kJ per ELM) are comparable to mitigated ELMs expected in ITER (Pitts et al 2011 J. Nucl. Mater. 415 (Suppl.) S957-64).

Although significant material losses in terms of ejections into the plasma were not observed, there is indirect evidence that some small droplets (similar to 80 mu m) were released. Almost 1 mm (similar to 6 mm(3)) of W was moved by similar to 150 ELMs within 7 subsequent discharges. The impact on the main plasma parameters was minor and no disruptions occurred. The W-melt gradually moved along the leading edge towards the high-field side, driven by j x B forces. The evaporation rate determined from spectroscopy is 100 times less than expected from steady state melting and is thus consistent only with transient melting during the individual ELMs. Analysis of IR data and spectroscopy together with modelling using the MEMOS code Bazylev et al 2009 J. Nucl. Mater. 390-391 810-13 point to transient melting as the main process. 3D MEMOS simulations on the consequences of multiple ELMs on damage of tungsten castellated armour have been performed.

These experiments provide the first experimental evidence for the absence of significant melt splashing at transient events resembling mitigated ELMs on ITER and establish a key experimental benchmark for the MEMOS code.

Progress at JET in integrating ITER-relevant core and edge plasmas within the constraints of an ITER-like wall

This paper reports the progress made at JET-ILW on integrating the requirements of the reference ITER baseline scenario with normalized confinement factor of 1, at a normalized pressure of 1.8 together with partially detached divertor whilst maintaining these conditions over many energy confinement times. The 2.5 MA high triangularity ELMy H-modes are studied with two different divertor configurations with D-gas injection and nitrogen seeding. The power load reduction with N seeding is reported. The relationship between an increase in energy confinement and pedestal pressure with triangularity is investigated. The operational space of both plasma configurations is studied together with the ELM energy losses and stability of the pedestal of unseeded and seeded plasmas. The achievement of stationary plasma conditions over many energy confinement times is also reported.

The Shakespearean Auteur and the Televisual Medium

In the wake offundamental shifts in television, programming and production have seen television creations which rival—even go beyond—standard cinema in scope, length and character development. This essay takes the distinctive approach of applying auteur theory to the small screen, exploring what understandings of the auteur might mean for a new era of television Shakespeare, and, as its case-study, considers the BBC’s Hollow Crown series. Characterized by a feature-film appearance, a multimillion pound budget, and an all-star cast, the series is exemplary of how television is now made; hence, the essay argues, the series needs to be investigated in relation to the most recent understandings of the medium. Central to this investigation is the way in which producer Sam Mendes’s vision imprintsitself upon each of the series’s four episodes, and the first part of the essay is accordingly concerned with his recognizable style and credentials as the series “showrunner.” However, Mendes’s is not the only auteurial stamp on the series, and the essay is equally concerned with how each of Mendes’s three co-directors places his or her auteurial signature on the Shakespearean source material in such a way as to lend each production a unique character. These individualized creative visions, the essay argues, unfold in concert with Mendes’s conceptualization of the series in its entirety. Ultimately, televisual auteurism is understood as a complex phenomenon that allows for more than one creative approach to be entertained.

Machine learning for transient discovery in Pan-STARRS1 difference imaging

Efficient identification and follow-up of astronomical transients is hindered by the need for humans to manually select promising candidates from data streams that contain many false positives. These artefacts arise in the difference images that are produced by most major ground-based time-domain surveys with large format CCD cameras. This dependence on humans to reject bogus detections is unsustainable for next generation all-sky surveys and significant effort is now being invested to solve the problem computationally. In this paper, we explore a simple machine learning approach to real-bogus classification by constructing a training set from the image data of similar to 32 000 real astrophysical transients and bogus detections from the Pan-STARRS1 Medium Deep Survey. We derive our feature representation from the pixel intensity values of a 20 x 20 pixel stamp around the centre of the candidates. This differs from previous work in that it works directly on the pixels rather than catalogued domain knowledge for feature design or selection. Three machine learning algorithms are trained (artificial neural networks, support vector machines and random forests) and their performances are tested on a held-out subset of 25 per cent of the training data. We find the best results from the random forest classifier and demonstrate that by accepting a false positive rate of 1 per cent, the classifier initially suggests a missed detection rate of around 10 per cent. However, we also find that a combination of bright star variability, nuclear transients and uncertainty in human labelling means that our best estimate of the missed detection rate is approximately 6 per cent.